Abstract
Background
The brain is one of the main target organs affected by hypertension. Impaired cerebral oxygenation during exercise is an indicator of cerebral dysfunction. We aimed to investigate whether cerebral oxygenation during exercise correlates with subclinical markers of early target organ damage in a population of middle-aged, newly diagnosed hypertensive and healthy individuals.
Methods
Carotid intima–media thickness (cIMT) was measured using ultrasound, arterial stiffness was estimated measuring the augmentation index and pulse wave velocity, and retinal vessel diameter was assessed via the central retinal-arteriolar and vein equivalent and retinal-arteriovenous ratio. Participants (n = 93) performed a 3-minute isometric handgrip exercise. Cerebral prefrontal oxygenation was measured continuously using near infrared spectroscopy. The average exercise responses in oxygenated hemoglobin (O2Hb), deoxygenated hemoglobin (HHb), and total hemoglobin (tHb) were assessed. Univariate analyses were performed; partial correlation was used to account for traditional cardiovascular risk factors to identify independent associations between cerebral-oxygenation indices and early markers of target organ damage.
Results
Mean cIMT was negatively correlated with the average exercise response in cerebral oxygenation (rhoO2Hb = −0.348, PO2Hb = 0.001; rhotHb = −0.253, Pthb = 0.02). Augmentation index was negatively correlated with cerebral oxygenation during exercise (rhoO2Hb = −0.374, P < 0.001; rhotHb = −0.332, P = 0.02), whereas no significant correlation was observed between pulse wave velocity and cerebral-oxygenation indices. In the adjusted analysis, cerebral oxygenation was correlated with central retinal arteriolar diameter (CRAE r = 0.233, P = 0.043).
Conclusions
Our novel findings suggest that indices of lower cerebral oxygenation during a submaximal physical task are associated with markers of early, subclinical target organ damage, namely increased cIMT, arterial stiffness, and arteriolar retinal narrowing in newly diagnosed, untreated, hypertensive individuals.
Keywords: arterial stiffness, carotid IMT, cerebral oxygenation, exercise, hypertension, hypertensive retinopathy, near infrared spectroscopy, retinal vessels
Graphical Abstract
Hypertension is characterized by structural and functional alterations of the micro- and macrovasculature. These changes result in increased central systolic blood pressure (SBP) and pulse pressure (PP), which are strongly associated with target end-organ damage, and the development of clinical cardiac, renal and cerebral disease.1 By affecting the brain, hypertension adversely impacts cognitive function2 and can lead to dementia.3 Hypertension-induced alterations in cerebrovascular autoregulation and insufficient blood/oxygen delivery to the brain contribute to the development of white matter lesions.4
The retinal vasculature has been suggested as an easily accessible microvascular bed that allows direct noninvasive visualization of the body’s mircrovasculature and can aid in the detection of microvascular changes in hypertension, independently of traditional risk factors.5 Changes in retinal vessel morphology have been associated with concurrent brain microvascular disease and can also aid to identify at-risk patients for cerebrovascular complications, likely due to shared embryologic origin of retina and brain.6 In addition, large vessel stiffening and atherosclerosis were found to confer higher risk for cerebral white matter hyperintensities, and correlate with lower performance on cognitive tests.7,8 Nevertheless, whether small and large vessel impairments correlate with early functional brain alterations, such as changes in cerebral oxygenation/perfusion is unknown. Decreased brain oxygenation, especially during exercise has been implicated as an adverse prognostic factor in patients with heart failure.9
Studying potential associations between cerebral oxygenation and the aforementioned markers of micro- and macro-circulatory impairment could improve our understanding of brain dysfunction due to hypertension, and aid in early diagnosis of cerebrovascular dysfunction in hypertension. Taking the above into account, the aim of our study was to explore potential links between cerebral oxygenation during a physical task (submaximal isometric exercise) and other markers of target organ damage, namely carotid intima–media thickness (cIMT), arterial stiffness, and retinal vessel morphology in middle-aged, newly diagnosed hypertensive and healthy normotensive individuals.
Methods
Participants
This study was approved by the institutional review board committee; procedures were conducted in accordance with the principles of Declaration of Helsinki and institutional guidelines. The study population consisted of consecutive patients attending our hypertension clinic and healthy volunteers with no known history of cardiovascular or other disease from the local community. Participation in the study was voluntary and all subjects signed an informed consent form. To investigate the true effect of essential hypertension on brain oxygenation with minimal confounding, in the hypertension group, we only included patients with a new diagnosis of hypertension (defined as office SBP ≥ 140 mm Hg and/or DBP ≥ 90 mm Hg; European Society of Hypertension guidelines) without any other comorbidities.10 To exclude masked or white-coat hypertension all prospective participants underwent 24-hour ambulatory blood pressure measurement. Patients with secondary hypertension were excluded from the study.
Methods
Participants were instructed to abstain from alcohol, caffeine, and intense physical activity for at least 12 hours before the study. Detailed past medical, social, and family history were obtained. BP was measured initially on both arms. Next, BP was measured an additional 3 times on the brachial artery of the arm with the higher BP (digital Microlife sphygmomanometer, Switzerland) during rest in the seated position. The BP values reported are the average values of the second and third measurement of the extremity with the higher BP. Blood samples were collected for blood hemoglobin, chemistry, and lipid profile measurement. Patients were equipped with a 24-hour ambulatory BP monitoring device (Spacelabs 90207, Snoqualmie, WA), were instructed to perform their usual daily activities and return to the office the following day.
The following day each participant came back and the data of the 24-hour ambulatory BP monitor were extracted. Those without masked or white-coat hypertension continued the study protocol. Next, subclinical indices of target organ damage were determined at rest, shortly prior to the exercise protocol. Common carotid artery images close the carotid bulb were obtained using ultrasound (ALOKA, Hitachi, Wallingford, CT) and cIMT was measured as the distance between the intimal-luminal and the medial-adventitial interfaces of the vessel represented as a double-line density on an ultrasound image.11 The cIMT values reported are the mean values of left and right cIMT. Applanation tonometry (SphygmoCor, Atcor, Sydney, Australia) was used to estimate central/aortic blood pressure and indices of arterial stiffness (namely augmentation index corrected for mean heart rate of 75 (Aix@HR75) and carotid-femoral pulse wave velocity).12 For assessment of the retinal vasculature, all patients underwent bilateral, nonmydriatic digital fundus photography (NIDEK AFC-230/210, San Jose, CA). Two photographs were obtained from each eye, and the best quality photograph was examined by 2 independent graders masked to the subjects’ identity and BP group assignment. Retinal vessel morphology was analyzed with a semiautomated computer program as previously described.13,14 Indices of the average retinal arteriole and venule diameters, namely the Central Retinal Arteriolar Equivalents (CRAE) and Central Retinal Venular Equivalents (CRVE), as well as their ratio (arteriovenous ratio, AVR = CRAE/CRVE) were calculated using the modified Parr and Hubbard formulas.15,16
Exercise protocol and cerebral oxygenation.
First, the participants were connected to the experimental equipment; NIRS (OxyMon, Artinis Medical Systems, Elst, Netherlands) for assessment of cerebral oxygenation. A photoplethysmographer (Finapres Medical Systems, Enschede, Netherlands) was used for continuous beat-by-beat measurement of hemodynamics during the exercise protocol.17 The NIRS sensor was placed over the prefrontal cortex, contra-laterally to the exercising arm. Following a 15- to 20-minute calibration, baseline (resting) measurements were recorded. Next, maximal voluntary contraction (MVC) was assessed on the dominant hand (with the elbow flexed at 90°), using a digital dynamometer (Biopac MP150, Biopac systems Inc, Goleta, CA) with the participant seated. After a subsequent 5-min rest, a 3-min isometric handgrip exercise at 30% MVC was performed. Throughout the protocol, changes in cerebral oxygenation were monitored using NIRS, by measurement of the micromolar (μΜ) relative change from baseline (resting conditions) for oxygenated hemoglobin (O2Hb), deoxygenated hemoglobin (HHb), and total hemoglobin (tHb). THb was used as a measure of regional cerebral blood volume.18
Statistical analysis
Continuous variables are presented as mean ± standard deviation (SD) for normally and median (interquartile range [IQR]) for non-normally distributed variables. Independent t-test and Mann–Whitney test were used to compare between groups differences, based on the variables’ distribution. Correlations between variables were examined using Pearson’s and Spearman’s tests, as appropriate. To adjust for potential confounders, we used the partial correlation method. Our model was adjusted for age, body mass index (BMI), smoking, low-density lipoprotein cholesterol (LDL) and glucose, all known to adversely impact vascular function.19 Variables which were not normally distributed were transformed using the logarithmic function. The significance level was set at P < 0.05. Data were analyzed with SPSS 24 software (SPSS Inc, Chicago, IL).
Results
Baseline characteristics
Overall, 93 individuals were included in our study. Fifty-two were newly diagnosed, never treated hypertensives (hypertensive group; median age 46.50 [37.5–51.75) years] and 41 were healthy normotensive individuals (normotensive group; median age 49.00 [37.5–53.5] years). None of the participants was taking any medications. All individuals were minimally active, except 2 individuals in each group that were recreationally active. There were no differences in anthropometric and laboratory variables between the 2 groups, except for BP levels as expected by study design (Table 1).
Table 1.
Baseline characteristics of study participants
| Variables | Study population (n = 93) | Hypertensive group (n = 52) | Normotensive group (n = 41) | p value |
|---|---|---|---|---|
| Age | 47 (37–53) | 46.50 (37.5–51.75) | 49.00 (37.5–53.5) | 0.5 |
| Male (%) | 51 (54.8%) | 29 (55%) | 22 (53%) | 0.25 |
| Smoking (%) | 29 (31.2%) | 15 (31.2%) | 14 (35%) | 0.7 |
| Body mass index (kg/m2) | 26.57 (24.5–29.41) | 26.37 (24.34–29.74) | 26.67 (24.55–28.71) | 0.838 |
| Hemoglobin (g/dL) | 14.4 (13.3–15.2) | 14.27 ± 1.51 | 14.30 ± 1.22 | 0.937 |
| Blood glucose (mg/dL) | 88.65 ± 9.73 | 86.96 ± 10.32 | 89.58 ± 8.93 | 0.451 |
| Uric acid (mg/dL) | 5.18 ± 1.45 | 5.05 (4.2–5.8) | 5.24 ± 1.44 | 0.746 |
| eGFR (Cockroft-Gault) (ml/min/1.73 m2) | 113 (109.9–123.1) | 122.56 (99–136) | 113.83 (100–134) | 0.932 |
| Total cholesterol (mg/dL) | 212 ± 43.78 | 212.90 ± 45.92 | 210.87 ± 41.48 | 0.833 |
| HDL-cholesterol (mg/dL) | 47 (41–52) | 46 (40–51) | 47 (42–52) | 0.7 |
| LDL-cholesterol (mg/dL) | 140.30 ± 37.57 | 140.85 ± 39.10 | 139.63 ± 36.11 | 0.883 |
| Triglycerides (mg/dL) | 101 (66–147) | 104.54 (64–156) | 94 (66–137) | 0.319 |
| MVC (kg) | 42.62 (32.16–56.22) | 47.09 ± 16.02 | 36.48 (27.97–53.80) | 0.105 |
| Office SBP (mm Hg) | 134.34 ± 16.5 | 145.24 ± 12.75 | 121.03 ± 9.11 | 0.000 |
| Office DBP (mm Hg) | 88.11 ± 11 | 95.98 ± 7.63 | 78.51 ± 5.74 | 0.000 |
| Office HR (bpm) | 73.63 ± 10.56 | 74.12 ± 12 | 73 ± 8.25 | 0.628 |
Values are presented as mean ± standard deviation or median (interquartile range). Abbreviations: eGFR, estimated glomerular filtration rate; HDL, high-density lipoprotein; LDL, low-density lipoprotein; MVC, maximal voluntary contraction; SBP, systolic blood pressure; DBP, diastolic blood pressure; HR, heart rate; bpm, beats per minute.
Subclinical markers of target organ damage
CIMT was not different between hypertensive and normotensive groups (Table 2). The hypertensive group had significantly higher PWV and aortic Aix@HR75, decreased CRAE and AVR compared with normotensive group. There was no difference in CRVE between groups. Finally, the hypertensive group exhibited a significantly lower rise in brain oxygenation during exercise, as evident by the lower average response in O2Hb (P = 0.046). No significant differences between groups were observed in the average HHb and tHb responses.
Table 2.
Target organ damage in hypertensive versus normotensive individuals
| Variable | Study population (n = 93) | Hypertensive group (n = 52) | Normotensive group (n = 41) | P value |
|---|---|---|---|---|
| Pulse wave velocity (m/s) | 7.51 ± 1.2 | 7.8 ± 1.24 | 7.05 ± 1.07 | 0.009 |
| Augmentation index (%) | 21.67 (10.17–29.58) | 24.66 (18.5–33.0) | 15.20 ± 12.89 | 0.002 |
| Mean carotid intima–media thickness (mm) | 0.55 (0.5–0.64) | 0.55 (0.49–0.64) | 0.59 (0.5–0.63) | 0.65 |
| Central retinal artery equivalent (μm) | 86.7 (81.58–98.16) | 84.02 (79.1–92.36) | 93.67 ± 11.9 | 0.001 |
| Central retinal vein equivalent (μm) | 119.14 (109.73–127.75) | 117.97(109.71–127.67) | 120.46 ± 16.65 | 0.57 |
| Retinal arteriovenous ratio | 0.76 ± 0.11 | 0.73 ± 0.09 | 0.78 ± 0.11 | 0.016 |
| Average cerebral response during exercise | ||||
| Oxygenated hemoglobin (μmol/L) | 1.88 (1.51–2.92) | 1.54 (1.06–2.75) | 2.74 (1.39–3.22) | 0.046 |
| Deoxygenated hemoglobin (μmol/L) | −0.29 (−0.64, −0.15) | −0.29 (−0.55, −0.17) | −0.30 (−0.67, −0.08) | 0.45 |
| Total hemoglobin (μmol/L) | 1.57 (0.81–2.38) | 1.24 (0.8–2.12) | 2.16 (0.75–2.81) | 0.1 |
Values are presented as mean ± standard deviation or median (interquartile range). Augmentation index normalized for a heart rate of 75 beats/min (%) is presented.
Correlation between markers of cerebral oxygenation during exercise with subclinical markers of other target organ damage
Cerebral oxygenation/regional blood volume changes during exercise and carotid IMT. In the total study population, the average cerebral O2Hb response during exercise was negatively correlated with mean cIMT (rhoO2Hb = −0.348, PO2Hb = 0.001, Figure 1A). In addition, mean cIMT was negatively correlated with the change in regional blood volume during exercise (rhotHb = −0.253, Pthb = 0.02, Figure 2A). There was no correlation between cIMT and HHb. In the adjusted model, mean cIMT remained correlated with O2Hb (r = −0.229, P = 0.045 for logO2Hb, Table 3). The correlation of tHb and mean IMT did not remain statistically significant in the adjusted model (Table 3). Next, subgroup analyses were performed. In the hypertensive group, the cerebral-oxygenation response during exercise and the regional blood volume change were negatively correlated with mean cIMT (with O2Hb: rhoO2Hb = −0.363, PO2Hb = 0.01, Figure 1B, with tHb: rhotHb = −0.364, Pthb = 0.02, Figure 2B). There was no correlation between mean cIMT and HHb. In adjusted model, mean cIMT was still significantly correlated with O2Hb (r = −0.364, P = 0.023 for logO2Hb, Table 3), whereas the correlation of tHb and mean cIMT did not remain statistically significant (Table 3). In the normotensive group, there was no significant correlation between mean cIMT and brain oxygenation during exercise (Figure 1C), HHb, or tHb (Figure 2C).
Cerebral oxygenation/regional blood volume changes during exercise and arterial stiffness. In the study population, Ai@75 was negatively correlated with cerebral oxygenation during exercise (rhoO2Hb = −0.374, P < 0.001, Figure 3A), tHb (rhotHb = −0.332, P = 0.02, Figure 4A), and there was a trend for a significant correlation with HHb (rho = 0.211, P = 0.055). The correlation between Ai@75 and O2Hb mean did not remain statistically significant in the adjusted model, whereas the correlation between tHb and Ai@75 remained statistically significant (r = −0.296, P = 0.01 for logtHb, Table 3). In the hypertensive group, there was a trend for a significant correlation between brain oxygenation during exercise and Ai@75 (rhoO2Hb = −0.274, P = 0.06, Figure 3B). HHb response during exercise significantly correlated with Ai@75 (rho = 0.421, p = 0.003), whereas no association between the change in regional cerebral blood volume during exercise and Ai@75 was found. In the normotensive group, there was a significant negative correlation between brain oxygenation, the change in regional blood volume during exercise and Ai@75 (with O2Hb: rho = −0.396, P = 0.015, Figure 3C; with tHb: rho = −0.544, P < 0.001, Figure 4C); however, no correlation between HHb and Ai@75 was found. In the adjusted model, the correlation between Ai@75 and average O2Hb did not remain statistically significant in the normotensive group (Table 3).
In the total population, there was a trend for a correlation between PVW and cerebral oxygenation (rho = −0.208, P = 0.057), whereas no correlation with tHb or HHb was observed. In the hypertensive group, PWV was not correlated with cerebral O2Hb and tHb. Similar to the hypertensive group, there was no correlation between PWV and cerebral O2Hb and tHb in the normotensive group.
Cerebral-oxygenation responses during exercise and retinal vessel morphology. In the study population, there was no significant correlation between brain oxygenation during exercise and retinal vessel morphology (CRAE, CRVE, AVR) in the univariate analysis. The partial correlation model showed a statistically significant correlation of cerebral O2Hb with CRAE (r = 0.233, P = 0.043 for logO2Hb), and no significant correlation between tHb and retinal vessel morphology analysis. In addition, in the study population negative correlation between HHb and CRVE (rho = −0.241, P = 0.026) was observed. In the hypertensive group, HHb was negatively correlated with CRVE (rhoCRVE = −0.309, PCRVE = 0.029), but not with CRAE, or AVR. However, the correlation between the average brain oxygenation response (O2Hb) during exercise and retinal vessel morphology (CRAE, CRVE, AVR) did not remain statistically significant in the subgroup analysis.
Figure 1.
Scatter plots showing the correlation between carotid intima–media thickness and oxygenated hemoglobin change during exercise in the study population (A) and in the hypertensive (B) and normotensive (C) groups.
Figure 2.
Scatterplots showing the correlation between carotid intima–media thickness and regional blood volume change (as reflected by tHb) during exercise in the total population (A) and in the hypertensive (B) and normotensive (C) groups.
Table 3.
Correlation between indices of cerebral oxygenation during exercise and markers of subclinical organ damage
| cIMT | Ai@75 | PVW | CRAE | CRVE | AVR | |
|---|---|---|---|---|---|---|
| Total population (n = 93) | ||||||
| O2Hb | −0.229* | −0.202 | 0.211 | 0.233* | 0.071 | 0.147 |
| tHb | −0.012 | −0.296* | 0.288 | 0.215 | −0.011 | 0.158 |
| Hypertensive group (n = 52) | ||||||
| O2Hb | −0.364* | 0.166 | 0.215 | 0.078 | −0.092 | 0.130 |
| tHb | −0.111 | −0.09 | −0.12 | 0.059 | −0.056 | 0.106 |
| Normotensive group (n = 41) | ||||||
| O2Hb | −0.048 | −0.155 | −0.076 | 0.223 | 0.242 | −0.019 |
| tHb | 0.116 | −0.208 | 0.260 | 0.134 | 0.202 | −0.028 |
The model was adjusted for age, BMI, smoking, LDL, and glucose. Numbers shown represent partial correlation coefficients. Abbreviations: cIMT, mean (left and right) carotid intima–media thickness; Ai@75, Augmentation index normalized for a heart rate of 75 beats/min; PVW, pulse wave velocity; CRAE, central retinal artery equivalent; CRVE, central retinal vein equivalent; AVR, arteriovenous ration; O2Hb, average response in oxygenated hemoglobin during exercise (relative changes from rest); tHb, average response in total hemoglobin during exercise.
*Statistical significance at 0.05 level.
Figure 3.
Scatterplots of the correlation between aortic augmentation index normalized for a heart rate of 75 beats per minute (aortic Ai@75) and oxygenated hemoglobin change during exercise in the total population (A) and in the hypertensive (B) and normotensive (C) groups.
Figure 4.
Scatterplots showing the correlation between aortic augmentation index normalized for a heart rate of 75 beats per minute (aortic Ai@75) and regional blood volume change (as reflected by total hemoglobin) during exercise in the total population (A) and in the hypertensive (B) and normotensive (C) groups.
Discussion
In this study, we investigated possible associations of cerebral prefrontal oxygenation during exercise with micro- and macrovascular markers of subclinical organ damage (i.e., intima–media thickness, arterial stiffness, and retinopathy) in middle-aged individuals with newly diagnosed hypertension and normotensive individuals. Our findings showed that early signs of both small and large vessel lesions correlate significantly with a reduced capacity to increase cerebral oxygenation during a physical task. More specifically, individuals with a blunted increase in cerebral oxygenation (as assessed by O2Hb) during exercise, exhibited greater signs of carotid atherosclerotic vascular disease (as evidence by the correlation with cIMT), increased vascular stiffness (as evident by greater augmentation index), and narrower caliber of the retinal arterioles.
The relationship between micro- and macrovascular impairment in hypertension is bidirectional.20 Hypertension-induced increase in arterial stiffness of the large arteries leads to increased blood flow pulsatility, which induces compensatory hypertrophy of the small vessels to respond to the elevated pulsatile load. Small vessel hypertrophy can lead to impaired vasoreactivity and hypoperfusion of target organs. On the other side, microvascular dysfunction can contribute to arterial stiffening. Impaired vasa vasorum of the large arteries result in large artery stiffening and remodeling20 and microvascular rarefaction increases peripheral vascular resistance,21 which increases arterial pressure. Elevated BP results in greater arterial stiffness, completing a self-perpetuating vicious circle.20
We found that individuals exhibiting a blunted increase in cerebral oxygenation during a physical task had greater signs of carotid atherosclerosis. Carotid IMT is a subclinical marker associated with endothelial dysfunction22 and increased incidence of stroke in patients with hypertension.23 Specifically, within the hypertensive group, we found a significant negative correlation between cIMT and changes in cerebral blood volume during exercise as reflected by tHb, as well as a negative correlation between cIMT and the increase in cerebral oxygenation during exercise. This is—to our knowledge—the first study to show that the decreased cerebral oxygenation with exercise is negatively correlated with cIMT. Two other studies reported that increased cIMT is negatively correlated with cerebral blood flow in the gray matter and the total brain.24,25 Of note, in our study the average cIMT did not differ between the hypertensive and normotensive groups, suggesting that the hypertensive group did not have overt atherosclerotic lesions in the carotids. Yet, a correlation between tHb and O2Hb with cIMT was only present in the hypertensive group. This may be indicative that endothelial dysfunction and reduced cerebral oxygenation during a demanding task precede the overt anatomical lesions of the carotid artery and represent even earlier markers of cerebrovascular health in hypertension. In a previous study, we showed that oxygen delivery and uptake are impaired in the skeletal muscle during exercise in newly diagnosed hypertensive individuals.26 In this study, we observed similar results for the brain. Taken together, these data suggest that there is a systemic dysfunction in oxygen delivery and utilization in hypertension from very early stages.
Stiffening of the large arteries decreases their ability to distend and store elastic energy in systole, energy that can maintain blood flow in diastole. Since less blood can be stored in these vessels, more blood has to be transported over longer distances, which requires higher driving pressures ultimately leading to wider pulse pressure. Increased arterial pressure and pulsatility impose higher mechanical stress on the vessels of different organs, which ultimately leads to end-organ damage.27 In this study, we observed a negative correlation between arterial stiffness and cerebral oxygenation during exercise as well as a negative correlation between arterial stiffness and regional blood volume changes to the brain. In the hypertensive group, HHb was positively correlated with arterial stiffness, while O2Hb showed a trend towards a negative correlation. These findings combined are suggestive of higher oxygen extraction in the hypertensive brain in the setting of decreased oxygen delivery as arterial stiffness increases. This is likely a compensatory mechanism to account for the reduced basal mean capillary blood flow seen in hypertensives,28 which is thought to protect from the increased blood pulsatility just upstream of the fragile capillary bed.29 Ultimately, this compensatory mechanism fails and structural brain damage ensues.29 These findings highlight the need for future studies to examine whether patients with increased arterial stiffness but without clinical or subclinical parenchymal brain disease could benefit from more aggressive blood pressure control to prevent strokes. In the normotensive group, we observed a negative correlation between arterial stiffness and the increase in cerebral oxygenated and total hemoglobin. Given that our normotensive group was healthy, free of any cardiovascular disease, the correlation of augmentation index and cerebral oxygenation further supports the role of augmentation index as an independent marker of vascular health in normotensive individuals.30 The negative correlation between arterial stiffness and tHb suggests that even otherwise healthy individuals can exhibit signs of decreased cerebral small vessel dilation during resistance exercise, as their large vessels stiffen.
Hypertensive retinopathy has been identified as an independent predictor of cardiovascular mortality31 and incidence of stroke32 in patients with hypertension. Additionally, focal arteriolar narrowing and small arteriovenous ratio have been correlated with the presence of subclinical cerebral infarcts on MRI.33 More recently, CRVE was shown to be an independent predictor of new onset stroke in hypertensive patients.34 In this study, we found that increased CRVE was negatively correlated with cerebral deoxygenation during an exercise challenge. Increased CRVE has been previously shown to be an independent predictor of lacunar strokes, which are common in hypertension.35 Additionally, increased retinal venular width has been associated with markers of vascular inflammation such as C-reactive protein.36 It is likely, that the early on in the course of hypertension oxygen utilization by the brain is impaired, which in the long-run leads to structural brain lesions. Prospective studies should evaluate whether a reduced capacity to activate the prefrontal cortex in hypertension is due to impaired local cerebral vessel autoregulation or excessive vasoconstriction, which together with proinflammation and procoagulation result in small vessel remodeling and ultimately lacunar strokes.37 We also noticed a weak correlation between CRAE and cerebral oxygenation in the partial correlation model. The weaker correlation between arteriolar caliber and risk for cerebrovascular events compared to the correlation between cerebrovascular events and retinal venule caliber is also supported by the Rotterdam study.38 Our study population consisted of newly diagnosed hypertensives without clinical cerebrovascular disease and healthy volunteers. It is likely that functional changes of the retinal vasculature could be more strongly correlated with the decrease in cerebral oxygenation during exercise than anatomic changes.
The present study has several strengths. First, our population consisted of newly diagnosed patients with hypertension with no other cardiovascular comorbidities. This allows us to draw conclusions about the effect of hypertension per se on the correlation of cerebral blood flow and oxygenation with subclinical damage in other target organs. Second, we only included patients with newly diagnosed hypertension and therefore we are able to draw conclusions on what happens early on in these patients. Limitations of our study include the cross-sectional design, which does not allow for temporal associations to be made and that we measured cerebral oxygenation over only one brain area and therefore did not assess potential changes in other parts of the brain.
In summary, our novel findings suggest that indices of cerebral oxygenation during a submaximal physical task are associated with markers of early, subclinical target organ damage, namely increased cIMT, arterial stiffness, and increased arteriolar narrowing in a population of newly diagnosed hypertensive individuals. This suggests that cerebral oxygenation and blood flow are impacted from the very early stages of hypertension along with impairments in other target organs. Prospective studies evaluating the progression of changes in cerebral oxygenation/blood flow in parallel to cIMT, arterial stiffness and hypertensive retinopathy, as well as the effect of antihypertensive treatment on brain oxygenation could help elucidate the pathogenesis of hypertension-related cerebrovascular disease.
DISCLOSURE
The authors declared no conflict of interest.
DATA AVAILABILITY
The data underlying this article will be shared on reasonable request to the corresponding author.
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Data Availability Statement
The data underlying this article will be shared on reasonable request to the corresponding author.